Air space distension precedes spontaneous fibrotic remodeling and impaired cholesterol metabolism in the absence of surfactant protein C

Surfactant protein C (SP-C) deficiency is found in samples from patients suffering idiopathic pulmonary fibrosis (IPF), especially in familial forms of this disease. In this study, we investigated the contribution of SP-C to alveolar cholesterol homeostasis and fibrotic remodeling in aging mice. For this purpose, we analyzed lung function, alveolar dynamics, lung structure, collagen content and expression of genes related to lipid and cholesterol metabolism of aging SP-C knock out mice. In addition, in vitro experiments with an alveolar macrophage cell line exposed to lipid vesicles with/without cholesterol and/or SP-C were performed. Alveolar dynamics showed progressive alveolar de-recruitment with age and impaired oxygen saturation. Lung structure revealed that decreasing volume density of alveolar spaces was accompanied by increasing of the ductal counterparts. Simultaneously, septal wall thickness steadily increased, and fibrotic wounds appeared in lungs from the age of 50 weeks. This remarkable phenotype is unique to the 129Sv strain, which has an increased absorption of cholesterol, linking the accumulation of cholesterol and the absence of SP-C to a fibrotic remodeling process. Overall loss of SP-C results in an age-dependent complex, heterogeneous phenotype characterized by a combination of over distended air spaces and fibrotic wounds that resembles CEPF (Combined Emphysema and Pulmonary Fibrosis) in IPF human patients. Addition of SP-C to cholesterol-laden lipid vesicles enhanced the expression of cholesterol metabolism and transport genes in an alveolar macrophage cell line, identifying a new lipid-protein axis involved in lung remodeling.